Unraveling Round Cell Sarcomas: A Contemporary Diagnostic Guide Beyond Ewing Sarcoma

Round cell sarcomas represent a continuously evolving category of malignant mesenchymal tumors, currently encompassing 5 main tumor subtypes: Ewing sarcoma, Capicua Transcriptional Repressor (CIC)-rearranged sarcoma, sarcomas with BCL6-corepressor (BCOR)-genetic abnormalities, POZ/BTB and AT hook containing zinc finger 1 (PATZ1)-rearranged sarcoma, and nuclear factor of activated T cells 2 (NFATC2)-rearranged sarcoma. These tumors show some degree of histomorphologic overlap, which, coupled with their infrequency, may render their diagnosis challenging for the pathologist. Furthermore, although ancillary techniques like immunohistochemistry and molecular tests can be of diagnostic aid, they are still limited by inherent sensitivity and specificity issues and cannot replace meticulous integration of clinical and radiologic findings. This review is focused on (1) providing a guide for tackling the diagnosis of round cell sarcomas and their mimics using an integrative approach combining demographics, clinicoradiologic data, histomorphology, and ancillary techniques and (2) detailing the most recent information on round cell sarcomas from the latest World Health Organization classification of Bone and Soft Tissue Tumors (fifth edition).